Normal tissue oxygen levels are critical to maintain homeostasis. Significant divergence from expected levels could serve as an indicator or confirmation of an underlying condition that may require intervention or more diligent monitoring. Despite the clinical significance and importance of tissue oxygenation levels in the diagnosis, prognosis, and treatment of several pathologies, there is clearly an unmet need for technologies to quantify tissue oxygen levels with a reasonable degree of accuracy, reliability, and robustness. The overall objective of this proposal is to bring the precision and consistency of electron paramagnetic resonance (EPR) oximetry to the clinical realm for easily-translatable measurements in cardiovascular, cancer, and cutaneous applications. In the past funding periods, we have discovered unique solid-state implants (probes) and procedures that enable unsurpassed accuracy and repeated interrogation of tissue oxygen levels at specific sites over a period of time, extending to months or longer. However, these measurements are limited primarily to laboratory research involving cells and small animals, the latter of which have known drawbacks in simulating human physiology. In the proposed funding period, we intend to build upon these innovations to translate this promising technology to the clinical realm. As a first ste toward this translation, we plan to develop at least three types of probes and procedures specifically intended for pO2 measurements in transcutaneous, subcutaneous, and deep tissue/organs. We will evaluate and validate the methods in pre- clinical, large animal models, and humans. We also propose to perform rigorous biocompatibility testing using a number of ISO/ASTM guidelines for implantable devices. The following specific aims are proposed: (i) Development of oxygen-sensing chips for continuous or long-term monitoring of pO2 in humans; (ii) Biocompatibility evaluation of oxygen-sensing chips for use in humans; (iii) Evaluation of oxygen-sensing chips for repeated pO2 measurements in preclinical animal models of disease and in humans; and (iv) Enabling technologies for making simultaneous oximetry measurements from multiple sites. When complete, the results from the proposed work will pave the way for subsequent clinical trials applying these innovative technologies for pO2 monitoring.